NLRP3 inflammasome inhibition with MCC950 improves insulin sensitivity and inflammation in a mouse model of frontotemporal dementia

NEUROPHARMACOLOGY

卷:180

Article

Hull, Claire¹  Dekeryte, Ruta¹  Buchanan, Heather¹  Kamli-Salino, Sarah¹  Robertson, Avril²  Delibegovic, Mirela¹  Platt, Bettina¹ 

[1] Univ Aberdeen, Inst Med Sci, Sch Med Med Sci & Nutr, Foresterhill, Aberdeen AB25 2ZD, Scotland

[2] Univ Queensland, Sch Chem & Mol Biosci, St Lucia, Qld 4072, Australia

关键词: Transgenic;    Knock-in;    Diabetes;    Insulin;    Dementia;    NLRP3;    Inflammasome;    ER stress;    UPR;    Inflammation;   

DOI  :  10.1016/j.neuropharm.2020.108305

来源: Elsevier

【 摘 要 】

The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome has been implicated as a crucial component in both neurodegeneration and diabetes. However, the role of metabolic signalling pathways and the NLRP3 inflammasome in frontotemporal dementia remain largely elusive. We therefore investigated the effects of an NLRP3 inhibitor (MCC950) in a murine tau knock-in (PLB2(TAU)) model vs. wild-type (PLBWT) control mice. In male PLB2(TAU) mice (4 months at start of study), MCC950 treatment (20 mg/kg, for 12 weeks) improved insulin sensitivity and reduced circulating plasma insulin levels. Further molecular analysis suggested normal-isation in insulin signalling pathways in both liver and muscle tissue. Treatment also resulted in improvements in inflammation and ER stress signalling, both peripherally and centrally, alongside a partial normalisation of phospho-tau levels. Overall, we provide evidence that MCC950 improved metabolic, inflammatory and frontotemporal dementia (FTD) relevant phenotypes in multiple tissues. NLRP3 inhibition may therefore offer a therapeutic approach to ameliorate FTD pathology.

【 授权许可】

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